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The  University  of  Chicago. 

Founded  by  JOHN  D.  ROCKEFELLER. 


On  the  Oxygen  Ethers  of  Urea* 


A  DISSERTATION 


SUBMITTED     TO     THE     FACULTIES     OF     THE    GRADUATE 

SCHOOLS    OF    ARTS,     LITERATURE,    AND    SCIENCE, 

IN  CANDIDACY  FOR  THE  DEGREE  OF  DOCTOR 

OF  PHILOSOPHY. 


DEPARTMENT  OF  CHEMISTRY. 


BY  WILLIAM  McAFEE  BRUCE. 


EASTON,  PA.  : 

Press  of  the  Chemical  Publishing  Co. 
1904. 


ON  THE  OXYGEN  ETHERS  OF  UREA. 


investigations  on  the  oxygen  ethers  of  the  ureas  as  carried 
on  in  this  laboratory  by  F.  B.  Dains1  and  R.  H.  McKee,2  under 
the  direction  of  Professor  Stieglitz,3  have  been  continued  by  me 
at  the  latter's  suggestion,  with  the  object  of  studying  the  isourea 
ethers  from  points  of  view  which  it  was  impossible  to  include 
in  the  work  done  by  Dains  and  McKee. 

A  more  detailed  study  was  first  made  of  the  chemical  nature 
of  the  acylisoureas.  Stieglitz  and  McKee4  found  that  by  the 
action  of  acylchlorides  on  monosubstituted  isoureas,  two  series 
of  isoureas  may  be  obtained,  the  symmetric  acylisourea  ethers, 

RCO.RHC(OR'):NR"     (I) 
and  the  asymmetric  ethers, 

RCO.NR"C(OR') :  NH     (II). 

These  ethers  are  very  sensitive  to  hydrogen  chloride,  which  in 
aqueous  solutions  at  low  temperatures  converts  them  into  acyl- 
ureas,  with  an  evolution  of  alkyl  chloride,  R'Cl.5  We  have  been 
able  to  show  that  the  loss  of  alkyl  chloride  is  always  preceded  by 
the  formation  of  hydrochlorides,  which  were  isolated  and  analyzed 
and  found  to  be  very  unstable.  In  some  cases  the  salts  lose  methyl 
or  ethyl  chloride  spontaneously  at  ordinary  temperatures.  The 
basic  character  of  the  acylisoureas  was  also  confirmed  by  the 
preparation  of  a  number  of  chlorplatinates. 

The  acylisourea  ethers  of  the  first  series  (I)  also  have  acid 
properties :  McKee  had  observed  that  methyl  benzoylphenyliso- 
urea  is  soluble  in  alkalies  as  well  as  in  acids,  but  had  not  under- 
taken the  isolation  of  any  of  these  salts.  We  have  been  able  to 
prepare  silver  and  sodium  salts  of  several  derivatives  of  this 
series,  thus  establishing  the  fact  of  their  dual  or  amphoteric  char- 
acter as  bases  and  acids.  On  the  other  hand,  we  found  that 

1J.  Am.  Chem.  Soc.,  ai,  136  (1899). 
2  Am.  Chem.J.,  26,  209  (1901). 

*  Ibid.,  ai,  101  (1899);  Ber.  d.  chem.  Ges.,  32,  1494  (1899);  33,  807  and  1517  (1900). 

*  Loc.  cit. 

6  Stieglitz,  McKee  :  Loc.  cit;  Wheeler  and  Johnson  :  Am.  Chem.  /.,  34,  216  (1900). 


143986 


acylisoureas  of  the  second  series  (II)  have  no  acid  properties. 
McKee's  observation  that  they  were  soluble  in  alkalies  was  con- 
firmed, but  it  could  be  readily  proved  that  in  dissolving  they  are 
saponified  to  the  acids  and  the  free  isoureas,  the  latter  of  which, 
as  will  be  shown  below,  again  have  the  property  of  forming  salts 
with  both  acids  and  bases. 

Acylisoureas  of  the  first  series  can  also  be  easily  obtained  by 
the  action  of  ammonia  or  amines  on  acylimido  monothiocarbonic 
ethers,  by  the  method  of  Miquel,1  as  improved  by  Loessner,2 
Dixon,3  and  especially  by  Wheeler  and  Johnson.4  The  formation 
of  metal  salts  of  these  symmetric  acylisoureas  and  the  ready 
saponification  of  the  asymmetric  acyl  derivatives  under  the  in- 
fluence of  alkalies  made  it  appear  possible  to  accomplish  the 
saponification  also  of  the  symmetric  acylisoureas  under  conditions 
which  would  permit  the  isolation  of  the  free  isourea  ethers  and 
thus  make  Dixon's  method  available  for  the  preparation  of  the 
isourea  ethers  themselves.  Such  a  method  would  be  desirable  as 
the  practical  variation  of  the  nature  of  the  alcohol  radical,  R' 
(see  I)  is  very  limited  in  our  present  methods  for  preparing 
isoureas  and  nearly  unlimited  in  Dixon's  method  of  preparing  the 
acyl  derivatives.  But  all  attempts  to  saponify  the  symmetric  acyl- 
isoureas without  completely  decomposing  the  isourea  radical  were 
unsuccessful;  very  small  quantities  or  none  of  the  free  isourea 
ether  could  be  isolated. 

Perhaps  the  most  interesting  observation  which  we  have  made 
on  the  acylisourea  ethers  is  that  we  have  been  able  to  verify  a 
suspicion  entertained  two  years  ago,  that  the  isomers  of  asym- 
metric series  (II)  are  rearranged  spontaneously,  but  gradually 
into  the  more  stable  symmetric  isomers  I.  The  action  is  as  fol- 
lows: 

RCO.NR"C(OR'):  NH  —  (NR"):  C(OR').NH(COR). 
The  rearrangement  is  entirely  analogous  to  other  migrations  of 
acyl  groups  from  oxygen  or  nitrogen  atoms  to  more  basic  neigh- 
boring amine  groups,  e.  g.,  to  the  rearrangement  of  orthoamino- 
phenylcarbonates  to  oxyphenylurethanes,  as  extensively  studied 

1  Ann.  chim.phys.,  (5)  n,  318  (1877). 
tj.prakt.  Chent.,  (2),  10,  237  (1874). 
*J.  Chem.  Soc.  (L,ondon),  75,  380  (1899). 
*  Loc.  cit. 


by  Stieglitz  and  Ransom,1  and  Stieglitz  and  Upson.2  The  rear- 
rangement is  also  analogous  to  that  of  the  isomeric  acylthioureas, 
as  studied  by  Professor  H.  L,.  Wheeler,3  and  in  order  not  to  inter- 
fere with  Professor  Wheeler's  investigations,  we  have  made  no 
further  study  of  the  rearrangement  of  our  asymmetric  acylisourea 
ethers  beyond  the  establishment  of  the  above  fact. 

In  their  work  on  the  oxygen  ethers  of  the  ureas  in  this  lab- 
oratory, Dains  and  McKee  studied,  in  particular,  to  what  extent 
these  ethers  exhibited  the  reactions  of  ethers  and  notably  of  the 
imido  ethers  to  which  they  are  closely  allied.  In  the  second  part 
of  this  work  attention  was  directed  especially  to  a  study  of  the 
character  of  the  isoureas  as  amidines.  Methylisourea,  as  its  con- 
stitution shows,  may  be  considered  to  be  an  amidoformimido 
ether,  or  methoxyformamidine.  The  study  was  especially  in- 
viting, because  in  one  important  particular  the  isoureas  seemed 
to  show  a  marked  difference  from  other  amidines  of  the  aliphatic 
series,  as  studied  by  Pinner.  This  was  in  the  fact  that  the  iso- 
ureas can  be  readily  isolated  as  free  bases  and  are  comparatively 
stable  bodies,  whereas  Pinner's  aliphatic  amidines  are  described 
as  very  unstable  bodies,  hardly  any  or  none  of  which  can  be  pre- 
pared as  free  bases.4  The  isoureas  give  the  most  important  reac- 
tions of  amidines.  In  particular  they  condense  very  readily  with 
yff-oxy  acid  esters  to  form  pyrimidines  according  to : 

(RO)(NH2)C  :  NH  -f  CH3C(OH):CHCOOR  — > 

NH.(RO)C  :  N.C(CH3):  CH.CO. 

i i 

They  also  form  condensation  products  with  oxalic  ether,  produc- 
ing oxygen  ethers  of  parabanic  acid : 

(RO)NH2.C  :  NH  +  (COOR)2  —  NH(RO).C  :N.CO.CO. 

\ 1 

They  form,  therefore,  a  very  convenient  starting-point  for  the 
synthesis  of  the  oxygen  ethers  of  the  ureides. 

Whereas  in  these  reactions  both  the  nitrogen  groups  react  read- 
ily— probably  on  account  of  the  great  tendency  to  form  five  and 

1  Am.  Ckem.J.,  23,  i  (1900). 

2  Vide,  a  later  report. 

3  Am.  Chem.J.,  37,  270  (1902). 

*  Pinner:  "  Imidoather,"  p.  90  (1892). 


six  atomic  rings — only  one  group  is,  as  a  general  rule,1  reactive 
when  no  ring  formation  occurs.  Thus  only  one  amine  group  is 
attacked  by  benzaldehyde — a  benzylidenediisourea  being  formed, 
viz. : 

C6H5CH[N:C(NH2)OCH3]2. 

Acetyl  chloride,  chlorcarbonic  ether  and  phenyl  mustard  oil 
also  react  with  but  one  amine  group. 

The  oxygen  ethers  of  phenylureas  were  also  found  to  form 
salts  with  metals  as  well  as  with  acids — a  property  which  is  char- 
acteristic of  amidines.2  In  these  salts  the  metal  is  held  by  a  nitro- 
gen atom. 

It  has  long  been  a  question  of  considerable  interest  to  us  to 
know  just  how  strong  the  oxygen  ethers  of  the  ureas  are  as  bases. 
It  seemed  very  possible  that  the  fundamental  difference  in  their 
behavior  as  contrasted  with  that  of  the  closely  related  group  of 
the  imidoethers  should  be  due  to  the  former's  greater  strength 
as  bases  and  their  ability  to  form  neutral  salts.3  It  was  also 
thought  that  it  would  be  of  interest  to  determine  quantitatively 
to  what  extent  the  basic  properties  of  the  ureas  are  increased  by 
converting  them  into  their  oxygen  ethers.  In  the  third  part  of 
this  investigation  the  affinity  constants  of  four  typical  isourea 
ethers — methyl  and  ethyl  isourea  and  methyl  and  ethyl  phenyl- 
isourea — were  determined  by  conductivity  methods.  The  results 
are  given  in  the  following  table,  together  with  the  constants  of 
urea4  and  several  other  bases,  for  purposes  of  comparison. 

K. 

Methyl  Amine io~  s  x  38.00 

Ethyl  Isourea io~  s  X  10.40 

Methyl  Isourea IQ-  s  X    6.40 

Ammonia io~  s  X    1.80 

Ethyl  Phenylisourea io~  s  x   0.05 

Methyl  Phenylisourea io~  *  X   0.02 

Aniline io~  8  X   °-°5 

Urea io-T3  X    0.15 

Guanidine  is  nearly  as  strong  a  base  as  the  alkalies.  Methyl 
and  ethyl  isourea,  as  mon-acid  bases,  are,  therefore,  of  about  the 
same  order  of  strength  as  ammonia  and  the  mon-alkyl  amines. 

1  The  only  exception  found  to  the  rule  is  that  two  molecules  of  phenylisocyanate  are 
taken  up  by  one  molecule  of  the  isourea. 

2  Bamberger:  Ann.  Chem.  (I^iebig),  273,  277  (1893). 
8  Stieglitz  :  Am.  Chem.J.,  ai,  106. 

*  See  page  115. 


In  spite  of  the  presence  of  two  amine  nitrogen  atoms  they  behave 
essentially  as  mon-acid  bases.1  They  have  also  exceedingly  small 
affinity  constants  for  a  second  molecule  of  acid,  evidence  of  which 
was  shown  in  the  conductivity  measurements  of  the  hydrochlo- 
rides  in  extreme  dilution  (see  Part  III)  and  in  the  tendency  of 
these  bases  to  form  solid  chlorides  containing  at  first  more  than 
one  equivalent  of  hydrochloric  acid.2 

It  is  noteworthy  that  the  change  of  urea  into  methyl  isourea, 

NH2CONH2  —  NH2C(.OCH3)NH 
has  increased  the  affinity  constant  of  the  basic  molecule  4  X  10*. 

EXPERIMENTAL  PART. 

I. .    TH£  ACYUSOUR3AS. 

The  acylisoureas  were  obtained  during  this  investigation  by 
two  methods:  First,  from  acyl  mustard  oils  by  the  method  of 
Miquel,  as  improved  by  Lossner,  Dixon,  and  Wheeler  and  John- 
son ;3  second,  the  method  of  Stieglitz  and  McKee.3 

The  first  method  is  very  much  the  longer  and  more  tedious, 
requiring  the  four  successive  reactions  after  the  preparation  of 
the  mustard  oils,  and  gives  smaller  yields  than  the  second  one. 

By  the  second  method  the  acylisoureas  are  very  readily  and 
simply  obtained  by  treating  the  isoureas  with  acyl  chlorides  and 
potassium  hydroxide.  The  isoureas  themselves  were  very  easily 
accessible  in  any  quantity  by  the  methods  of  Stieglitz  and  Dains, 
and  Stieglitz  and  McKee.  In  some  cases  these  have  been  made 
still  more  rapid  and  convenient  by  modifications  by  Dr.  R.  H. 
McKee  of  some  of  the  experimental  conditions  originally  used. 
These  modifications  have  not  yet  been  published  by  Dr.  McKee, 
but  they  were  kindly  furnished  to  me  by  the  latter  while  this 
work  was  in  progress.  The  first  new  acylisourea  prepared  was 
the  methyl  ether  of  symmetrical  w-nitrobenzoylphenylisourea.  It 
was  prepared  in  the  hope  that  the  strong  negative  character  of  the 
acyl  radical  would  make  it  easy  to  saponify  the  body  and  in  the 
expectation  that  it  would  prove  to  be  a  solid  which  would  serve 
as  a  rapid  and  convenient  test  for  the  presence  of  methyl  phenyl- 

1  Vide  Bredig  :  Ztschr.  phys.  Chem.,  13,  289  (1894). 

2  Am.  Chem.J.,  a6,  217  (1901). 
»  Loc.  tit. 


8 

isourea  in  oily  mixtures.  Only  the  latter  expectation  was  ful- 
filled. 

m-Nitrobenzoylsulphocarbimide,  m-NO2CQH4CONCSf  was  pre- 
pared from  25  grams  dry  lead  sulphocyanate  (about  twice  the 
theoretical  amount)  and  12.5  grams  w-nitrobenzoyl  chloride  in 
the  presence  of  dry  benzene,  according  to  the  general  method  of 
Dixon.1  It  was  purified  by  fractional  precipitation  by  petroleum 
ether  and  recrystallization  from  the  same  solvent.  It  melts  at 
94°.  The  analysis  gave  13.58  per  cent.  N;  calculated,  13.49  per 
cent. 

Methyl  m-Nitrobenzoylthio  carbonate, 

m-N02C.H,CONC(SH)  OCHZ. 

—  The  greater  part  of  the  benzene  solution  of  the  carbimide  ob- 
tained in  the  last  experiment  was  mixed  with  a  slight  excess  of 
anhydrous  methyl  alcohol  and  the  mixture  was  uently  warmed 
on  the  water-bath  and  set  aside  for  a  few  hours.  Masses  of  light 
yellow  crystals  of  the  appearance  of  velvet  buttons  were  then  ob- 
served. These  crystals  were  recrystallized  from  hot  80  per  cent. 
alcohol.  The  substance  melted  at  120°.  3.5  grams  of  the  pure 
substance  were  obtained.  Upon  evaporation  the  benzene  solution 
left  4  grams  of  a  light  yellow  solid,  which  melted  at  70°.  This 
was  methyl  w-nitrobenzoate. 

Analysis  of  the  crystals  melting  at  120°  gave  the  following 
figures:  n.86  per  cent.  N.  ;  calculated  for  C9H8O4N2S,  11.64 
per  cent. 

About  3.25  grams  of  the  carbonate  were  suspended  in  a  little 
anhydrous  methyl  alcohol  and  the  calculated  amount  of  potassium 
hydroxide  dissolved  in  the  minimum  amount  of  methyl  alcohol 
was  added.  Thin,  small  scales  of  the  potassium  salt  were  precip- 
itated. The  salt,  which  is  very  soluble  in  water,  was  filtered  off, 
washed  with  absolute  ether  and  dried  on  a  clay  plate.  The  yield 
was  3  grams.  Some  of  the  salt,  when  heated,  decomposed  at 
about  260°. 

Methyl  Ethyl  m-Nitrobenzoylimidothiocarbonate, 


—  Three  grams  of  the  above  salt  were  suspended  in  a  little  abso- 
lute methyl  alcohol  and  the  calculated  quantity  (1.7  grams)  ethyl 

1  Loc.  tit. 


iodide  added.  The  needle-like  crystals  which  formed  over  night 
were  recrystallized  from  methyl  alcohol.  The  melting-point  was 
constant  at  78°.  By  evaporation  another  crop  of  the  crystals  was 
obtained  from  the  mother-liquid.  The  analysis  gave  10.65  Per 
cent.  N. ;  calculated,  10.47  P61"  cent- 

Sym-.  O-Methyl  m-Nitrobenzoylphenylisourea, 

m-NO,CQH,CONC  (OCHZ)  NHC6H5. 

— This  substance  was  prepared  from  the  above  compound  and 
aniline,  according  to  the  method  of  Wheeler  and  Johnson1  for  the 
preparation  of  methyl  benzoylphenylisourea.  Mercaptan  was 
evolved  and  a  dark-colored  oil  remained  which  amounted  to  nearly 
the  calculated  quantity  for  the  isourea.  When  cooled  in  a  freez- 
ing mixture,  the  oil  solidified.  The  solid  was  washed  with  pe- 
troleum ether,  dissolved  in  chloroform  and  reprecipitated  by  pe- 
troleum ether.  The  substance  now  had  the  form  of  needles,  which 
melted  at  124°. 

The  same  compound  was  also  prepared  much  more  easily  from 
methyl  phenylisourea,  according  to  Stieglitz  and  McKee,  as  fol- 
lows: A  mixture  of  I  gram  methyl  phenylisourea  in  15  cc.  of 
alcohol-free  ether  and  0.4  gram  potassium,  hydroxide  in  0.5  cc. 
water  was  cooled  to  o°  and  treated  with  1 .2  grams  w-nitrobenzoyl 
chloride  dissolved  in  a  little  absolute  ether.  A  white  flocculent 
substance  separated.  The  ether  was  poured  off  and  the  residue 
extracted  several  times  with  more  ether.  The  crystalline  residue, 
insoluble  in  ether,  was  thoroughly  washed  with  water.  The  yield 
was  i  gram  and  the  melting-point  120°.  Precipitated  from  a 
chloroform  solution  by  petroleum  ether,  the  substance  was  ob- 
tained in  the  form  of  colorless  needles,  which  melted  at  124°. 
Some  of  these  crystals  were  mixed  with  those  obtained  by  the 
method  of  Wheeler  and  Johnson,  and  the  melting-point  was  un- 
changed. The  ether  extracts  above  obtained  were  now  examined 
to  see  if  they  contained  and  isomeric  methyl  w-nitrobenzoylphenyl- 
isourea,  The  ether  was  evaporated  and  0.3  to  0.4  gram  of  a  some- 
what mucilaginous  solid  was  left,  which,  after  recrystallization, 
proved  to  be  identical  with  the  substance  already  obtained,  which 
melted  at  124°.  The  latter  was  analyzed  and  gave  14.08  per  cent. 
N ;  calculated,  14.07  per  cent. 

i  Loc.  cit. 


10 

Sym.  m-Nitrobenzoylphenylurea, 

m-N02C6HtCONCONHC6H6. 

— A  small  amount  of  the  isourea  was  decomposed  by  dry  hydro- 
gen chloride  at  90°  to  130°  and  gave  methyl  chloride  and  sym. 
w-nitrobenzoylphenylurea.  The  latter  was  purified  by  repeated 
extraction  with  boiling  alcohol  or  by  recrystallization  from  a  large 
quantity  of  boiling  alcohol.  It  formed  very  fine,  colorless  needles, 
soluble  in  hot  water,  little  soluble  in  ether  and  melting  at  224° 
to  a  clear  colorless  liquid.  The  same  substance  also  may  be  ob- 
tained from  the  isourea  by  the  action  of  warm  concentrated  hy- 
drochloric acid.  The  analysis  gave  14.88  per  cent.  N ;  calculated, 
14.77  Per  cent- 

Action  of  Potassium  Hydroxide  on  Sym.  O -Methyl  m-Nitro- 
benzoylphenylisourea. — Very  many  attempts  were  made  to  saponify 
the  acylisourea  in  the  hope  of  developing  a  new  method  of  prepar- 
ing isoureas.  Potassium  hydroxide  and  weaker  bases  (e.  g.,  lead 
hydroxide)  were  used  in  aqueous  and  alcoholic  mixtures  in  the 
cold  and  at  elevated  temperatures.  The  saponification  was  ob- 
served to  go  with  difficulty  and  to  result  in  the  almost  total  de- 
composition of  any  isourea  that  may  have  been  first  formed.  Only 
very  small  quantities  of  the  isourea  were  isolated.  A  single  ex- 
periment will  illustrate  the  process  used. 

Three  grams  methyl  w-nitrobenzoylphenylisourea  were  boiled 
for  one  hour  under  a  reflux  condenser  with  0.7  gram  (i  mol.  +) 
potassium  hydroxide  in  10  cc.  water;  a  little  more  of  the  alkali 
was  gradually  added,  as  the  action  seemed  slow.  Most  of  the  sub- 
stance finally  passed  into  solution.  The  whole  solution  became 
dark  red  in  color  and  smelled  of  aniline  and  ammonia.  Upon 
cooling,  a  dark  red  gum  separated  out,  but  was  not  removed. 
Ten  grams  potassium  hydroxide  were  now  added  and  the  solu- 
tion extracted  with  ether.  A  dark  red  solid  remained  undissolved 
by  the  ether.  This  solid  was  dissolved  in  water  and  the  solution 
acidified  with  hydrochloric  acid.  A  brown  mucilaginous  precip- 
itate was  obtained.  This  was  washed  with  alcohol  and  gave  a 
yellow  powder,  which  did  not  melt  when  heated  to  270°,  but  black- 
ened. The  acid  solution,  when  cooled  with  ice,  gave  another 
considerable  precipitate,  which  melted  sharply  at  140°,  even  when 
mixed  with  m-nitrobenzoic  acid.  The  ether  was  distilled  from 
the  ether  extract  and  a  small  amount  of  a  reddish  oil  remained 


II 

which  contained  some  colorless  crystals.  The  oil,  when  tested 
for  aniline  with  nitrous  acid,  gave  a  strong  phenol  odor  and  a  deep 
red  oil.  The  remainder  of  the  reddish  oil  was  taken  up  in  petro- 
leum ether;  the  colorless  crystals  remaining  melted  at  147°,  and 
when  mixed  with  phenyl  urea  still  melted  at  147°.  The  petroleum 
ether  was  distilled  off  and  the  oil  which  was  left  gave,  when 
treated  with  dry  hydrogen  chloride,  no  methyl  chloride.  Hence 
no  isourea  was  present.  A  very  little  of  the  oil  gave  a  strong 
test  for  aniline  with  bleaching-powder.  The  chief  products  of 
the  reaction — w-nitrobenzoic  acid  and  aniline — showed  that  com- 
plete decomposition  of  the  acylisourea  had  occurred. 

Sym.  O-Methyl  Benzoylphenylisourea, 

CQH5CONC(OCH3)NHCQH,. 

— This  compound,  which  had  been  prepared  both  by  Wheeler  and 
Johnson,  and  by  McKee  and  described  by  them  as  an  oil,  was 
obtained  in  the  form  of  fine  needles,  which,  when  pure,  melt  at 
50°.  5.8  grams  dimethyl  benzoylimidothiocarbonate  were  con- 
verted into  the  benzoylisourea  ether  by  treatment  with  aniline, 
according  to  the  method  of  Wheeler  and  Johnson.  The  resulting 
oil  was  set  aside  and  after  one  day  fine  yellow  crystals  began  to 
separate  in  the  form  of  needles  which,  in  one  day  more,  penetrated 
the  whole  mass.  As  the  quantity  of  these  crystals  did  not  in- 
crease after  standing  several  weeks,  the  substance  was  exposed 
all  day  to  the  winter  cold  ( — 10°)  and  the  whole  mass  solidified. 
The  solid  was  purified  by  cooling  a  concentrated  methyl  alcohol 
solution  of  it  in  a  freezing-mixture.  The  pure  crystals  melt  at 
50°  and  evolve  methyl  chloride  almost  quantitatively  when  treated 
with  dry  hydrogen  chloride.  Some  of  the  substance  in  petro- 
leum ether  solution  was  treated  with  hydrogen  chloride  and  a 
precipitate  was  obtained  which,  when  purified,  melted  at  205°, 
the  melting-point  of  sym.  benzoylphenylurea.  This  proves  that 
the  substance  melting  at  50°  is  symmetrical  methyl  benzoylphenyl- 
isourea. 

'ilie  same  compound  was  also  prepared  by  McKee's  method 
and  obtained  in  crystalline  form. 

Action  of  Potassium  Hydroxide  on  O-Methyl  Benzoylphenyl- 
isourea. — Six  grams  of  the  isourea  were  mixed  with  1.4  grams 
(i  mol.)  potassium  hydroxide  in  25  cc.  water  and  vigorously 
boiled  under  a  reflux  condenser  for  about  a  half  hour.  Some  of 


12 

the  oil  was  then  taken  out  and  tested  with  hydrochloric  acid.  As 
the  formation  of  benzoylphenylurea  showed  that  a  considerable 
quantity  of  the  original  isourea  was  still  present,  5  cc.  of  alcohol 
and  i  gram  more  of  potassium  hydroxide  were  added  and  the 
boiling  continued  for  another  half  hour.  During  the  boiling  a 
strong  odor  of  ammonia  was  observed.  All  the  oil  finally  disap- 
peared. After  the  addition  of  15  grams  of  potassium  hydroxide 
to  the  cold  solution  a  white  crystalline  solid  separated  out.  This 
was  filtered  off,  washed  with  ether  and  dried.  The  amount  was 
1.5  grams.  This  solid  was  dissolved  in  water  and  the  solution 
acidified  with  dilute  hydrochloric  acid.  Benzoic  acid  was  pre- 
cipitated (m.  p.  122°).  The  alkaline  solution  was  extracted  sev- 
eral times  with  ether  and  then  acidified  with  hydrochloric  acid; 
more  benzoic  acid  was  precipitated.  The  ether  solution  was  dried 
with  freshly  ignited  sodium  sulphate  and  the  ether  distilled 
off.  A  thick,  light  yellow  oil  remained.  When  tested  with  con- 
centrated hydrochloric  acid  the  oil  showed  the  presence  of  a  small 
amount  of  the  original  methyl  benzoylphenylisourea.  Some  of 
the  residue  was  washed  with  dilute  acetic  acid  and  gave  a  solid, 
which  melted  at  155°.  Some  of  this  solid  was  mixed  with  benz- 
anilide  (m.  p.  161°)  and  the  mixture  still  melted  at  155°.  The 
remainder  of  the  oil  was  extracted  with  petroleum  ether,  which, 
upon  evaporation,  left  1.4  grams  of  an  oil.  The  oil  was  distilled 
at  10-20  mm.  pressure  and  part  of  the  material  came  over  at  100°, 
but  nothing  more  distilled,  although  the  bath  was  heated  to  220°. 
The  distillate  boiled  under  atmospheric  pressure  at  183°  and  a 
few  drops  treated  with  benzoyl  chloride  gave  benzanilide  (m.  p, 
161°,  unchanged  by  synthetic  benzanilide).  The  above  residue, 
insoluble  in  petroleum  ether,  was  dissolved  in  ether  and  I  mol. 
(calculated  for  methyl  phenylisourea)  of  potassium  hydroxide 
in  i  cc.  of  water  was  added.  The  whole  was  then  cooled  to  o° 
and  i  mol.  -m-nitrobenzoyl  chloride  in  absolute  ether  was  slowly 
added.  The  ether  solution  was  then  poured  off  and  the  ether  was 
evaporated.  The  white,  gummy  mass  remaining  was  purified  by 
treating  a  chloroform  solution  of  it  with  petroleum  ether.  A 
very  small  amount  of  a  substance  was  obtained,  which  melted  at 
124°.  The  melting-point  was  not  changed  when  it  was  mixed 
with  w-nitrobenzoylphenylisourea.  It  follows  that  the  substance 
which  reacted  with  the  w-nitrobenzoyl  chloride  was  methyl  phenyl- 


isourea.    But  it  formed  only  a  very  small  part  of  the  products  of 
the  reaction.    It  must  have  been  formed  as  follows : 
C6H5CONC(OCH3)NHC6H5  +  KOH  — » 

C6H5NHC(OCH3):  NH  +  C6H5COOK. 

Many  other  experiments,  varying  all  possible  conditions,  were 
made  on  the  saponification  of  methyl  benzoylphenylisourea  for 
the  purpose  of  improving  the  yield  of  the  phenylisourea,  but  noth- 
ing more  than  a  trace  was  ever  obtained. 

It  was  found  by  Dixon  that  when  methyl  benzoylisourea  was 
boiled  with  a  large  excess  of  aqueous  potassium  hydroxide  com- 
plete saponification  to  benzoic  acid,  alcohol,  carbon  dioxide  and 
ammonia  occurred.  My  results  on  the  action  of  alkalies  on  methyl 
benzoylphenylisourea  also  show  complete  saponification  of  the 
molecule,  with  a  destruction  of  the  urea  radical. 

Silver  Salt  of  sym.  Methyl  Benzoylphenylisourea, 
CQH5C(OAg) :  N.C(OCHS) :  NC«H5. 

— Silver  nitrate  (0.25  gram,  a  little  less  than  I  molecule)  dissolved 
in  8  cc.  of  50  per  cent,  methyl  alcohol  was  slowly  added  to  a 
mixture  of  methyl  benzoylphenylisourea  (0.4  gram  dissolved  in 
10  cc.  methyl  alcohol)  and  sodium  methylate  (from  0.07  gram 
sodium  and  10  cc.  methyl  alcohol).  A  little  silver  oxide  which 
formed  was  filtered  off  and  the  filtrate  was  treated  with  water; 
a  white  precipitate,  very  difficult  to  purify,  was  obtained.  The 
substance  was  thoroughly  washed  with  water  and  ether  and  dried 
on  a  clay  plate  in  vacuo.  A  silver  determination  gave  30.50  per 
cent.  Ag. ;  calculated  for  C15H13O2N2Ag,  29.92  per  cent. 

The  silver  salt,  when  treated  with  methyl  chloride,  gave  chiefly 
methyl  benzoylphenylisourea  again,  no  alkylation  of  the  substance 
being  produced.  The  recovered  benzoylphenylisourea  gave  methyl 
chloride  and  benzoylphenylurea  (m.  p.  205°)  and  formed  a  plat- 
inum salt  which  gave  21.24  Per  cent-  platinum;  calculated,  21.24 
per  cent. 

O -Methyl  Benzoylisourea  Hydro  chloride, 

C6H5CONHC(OCH3)NH.HCl. 

— Methyl  benzoylisourea  (0.5  gram)  was  dissolved  in  absolute 
ether  and  dry  hydrogen  chloride  passed  into  the  solution.  The 
precipitate  was  filtered  off,  washed  with  absolute  ether  and  dried 
in  a  vacuum  over  concentrated  sulphuric  acid  and  solid  potassium 


hydroxide.  The  salt  now  evolved  methyl  chloride  when  heated 
to  50°.  The  methyl  benzoylisourea  itself,  when  treated  with  dry 
hydrogen  chloride  without  a  diluent,  gave  off  methyl  chloride  at 
ordinary  temperatures.  Chlorine  determinations  of  the  salt  freshly 
prepared,  and  as  dried  for  two  days,  gave  16.46  and  16.06  per 
cent.  Cl. ;  calculated,  16.50  per  cent. 

Hence,  in  the  course  of  two  to  three  days  the  salt  must  have 
undergone  some  decomposition  with  the  loss  of  methyl  chloride. 
This  conclusion  is  further  confirmed  by  the  fact  that  when  II 
was  prepared  for  analysis,  a  slight  amount  of  the  substance 
was  found  to  be  insoluble  in  water,  whereas  I  dissolved  im- 
mediately and  completely. 

The  Sodium  Salt  of  O-Methyl  Benzoylisourea, 
CQH5C(ONa) :  N.C(OCH3) :  NH. 

— The  isourea  (0.5  gram)  was  dissolved  in  the  least  possible 
quantity  of  absolute  methyl  alcohol  and  a  slight  excess  of  sodium 
methylate,  dissolved  in  the  minimum  amount  of  dry  methyl  alco- 
hol, was  added.  An  oil  was  precipitated  which,  after  standing 
for  some  time,  solidified.  In  another  experiment  the  oil  solidified 
at  once  when  seeded  with  a  little  of  the  sodium  salt.  The  yield 
was  quantitative.  The  analysis  gave  1 1 .86  per  cent.  Na. ;  calcu- 
lated, 11.50  per  cent. 

As  in  the  case  of  the  silver  salt  of  benzoylphenylisourea  methyl 
ether,  all  attempts  to  methylate  the  sodium  salt  led  to  the  forma- 
tion of  the  original  substance,  benzoylisourea. 

Action  of  Acetyl  Chloride  on  Methyl  Phenylisourea. 

Five  grams  methyl  phenylisourea  were  dissolved  in  25  cc.  ether 
and  2  grams  ( I  mol.  +  )  potassium  hydroxide  in  2  cc.  water  were 
added  and  the  mixture  cooled  by  ice-water.  The  flask  was  then 
removed  from  the  cold  water  and  2.7  grams  (i  mol.)  acetyl  chlo- 
ride added  at  once  and  the  whole  well  shaken  for  about  half  an 
hour  or  until  all  the  acetyl  chloride  was  used  up.  The  ether  solu- 
tion was  filtered  off  and  the  residue  extracted  several  times  with 
ether,  the  extracts  being  added  to  the  first  filtrate.  The  ether 
solution  was  dried  with  anhydrous  sodium  sulphate,  filtered  and 
evaporated  in  vacuo.  A  white  solid  was  left,  mixed  with  a  little 
clear,  colorless  oil.  The  oil  was  taken  up  in  a  little  petroleum 


15 

ether,  most  of  the  solid  (X)  remaining.  When  the  petroleum 
tion  washed  with  a  little  water,  then  with  a  very  little  dilute 
(X)  and  (Y),  as  will  be  proved  presently,  are  the  isomeric  methyl 
acetylphenylisoureas.  In  the  solid  (X)  the  acetyl  and  phenyl 
groups  are  attached  to  the  same  nitrogen  atom,  and  in  the  oil  (Y) 
these  groups  are  bound  to  different  nitrogen  atoms. 

Sy m.  O -Methyl  Acetylphenylisourea, 

CH3CONHC(  :NCQH5)OCHZ. 

— The  oil  ( Y)  was  dissolved  in  alcohol-free  ether,  the  ether  solu- 
tion washed  with  a  little  water,  then  with  a  very  little  dilute 
hydrochloric  acid  to  remove  any  excess  of  methyl  phenylisourea, 
then  three  more  times  with  a  little  water.  It  was  finally  thor- 
oughly dried  with  freshly  ignited  sodium  sulphate.  Nearly  all 
the  ether  was  evaporated  and  the  remaining  ether  solution  de- 
canted from  a  few  crystals  which  had  separated,  and  the  ether 
completely  evaporated.  An  oil  was  left  which,  when  exposed  all 
day  to  the  winter  cold,  showed  no  tendency  to  solidify.  The  com- 
pound was  identified  in  the  following  way :  A  small  amount  was 
dissolved  in  absolute  ether  and  dry  hydrogen  chloride  passed  into 
the  cold  solution ;  a  white  precipitate,  which  formed  at  once,  was 
filtered  off  and  placed  on  a  clay  plate  in  vacua  for  two  days.  The 
substance  then  melted  at  I25°-I55°.  Washed  with  alcohol  and 
dried,  the  compound  melted  at  182°  to  a  clear  colorless  liquid 
and  when  mixed  with  synthetic  sym.  acetylphenylurea  it  still 
melted  at  182°.  Hence,  the  original  oil  (Y)  was  symmetrical 
O-methyl  acetylphenylisourea.  The  latter  when  treated  in  ether 
solution  with  hydrogen  chloride  either  reacted  at  once,  giving 
the  corresponding  urea,  or  else  the  hydrochloride  was  first  formed 
and  then  spontaneously  decomposed  when  left  in  vaciw  for  two 
days.  Experiment  showed  that  the  former  reaction  takes  place, 
the  methyl  acetylphenylurea  being  formed  at  once  from  the 
corresponding  isourea.  The  hydrochloride  itself  is,  under 
these  conditions,  entirely  unstable.  Some  of  the  oil  (Y)  when 
treated  with  dry  hydrogen  chloride  evolved  methyl  chloride  when 
heated  to  60°. 

Two  attempts  further  to  identify  the  sym.  methyl  acetylphenyl- 
isourea by  analysis  gave  low  results  for  nitrogen,  which  showed 
that  the  substance  was  not  obtained  absolutely  pure.  Analytical 


i6 

evidence  identifying  it  completely  was  obtained,  however,  by  the 
preparation  and  analysis  of  its  chlorplatinate. 

Some  of  the  oil  (Y)  was  dissolved  in  absolute  ether  and  the 
calculated  quantity  of  hydrochlorplatinic  acid  dissolved  in  a  little 
absolute  alcohol  added.  A  light  yellow  crystalline  precipitate 
formed  immediately.  This  precipitate  was  washed  several  times 
with  absolute  ether  and  dried  for  half  an  hour  over  concentrated 
sulphuric  acid  and  solid  potassium  hydroxide.  It  then  gave  24.73 
and  24.17  per  cent.  Pt;  calculated  for  C20H28O4N4PtCl6,  24.54 
per  cent. 

Asym,  O -Methyl  Acetylphenylisourea, 

CH,CO(CQH,)NC( :  NH)OCH3. 

— The  solid  (X),  recrystallized  several  times  from  boiling  petro- 
leum ether,  was  obtained  in  the  form  of  long,  beautiful,  rhombic 
prisms  which  melt  at  102°  and  are  very  soluble  in  chloroform, 
benzene,  acetone  and  alcohol,  quite  easily  in  ether,  but  somewhat 
less  soluble  in  petroleum  ether.  The  analysis  gave  14.25  per  cent. 
N. ;  calculated,  14.58  per  cent. 

Asym.  Acetylphenylurea,  CH3CONC6H5CONH2.—The  ether 
(X),  0.5  gram,  was  treated  with  dry  hydrogen  chloride.  Methyl 
chloride,  which  began  to  form  at  ordinary  temperature,  was  ob- 
tained in  quantity  (35  cc.)  under  the  influence  of  gentle  heat,  and 
asym.  acetylphenylurea  was  left  as  a  white  solid  in  the  reaction 
vessel.  It  was  recrystallized  twice  from  hot  water  and  obtained  in 
the  form  of  fine  needles.  These  melted  at  167°  to  a  turbid  liquid 
as  if  on  melting  there  had  been  decomposition.  Mixed  with  sym. 
acetylphenylurea  (m.  p.  183°)  the  melting-point  was  depressed  to 
154°. 

Asym.  O-M  ethyl  Acetylphenylisourea  Hydro  chloride, 

CH3CON(CQH5)C( :  NH)OCHSHCI. 

— The  asym.  acylisourea,  i  gram,  was  dissolved  in  absolute  ether 
and  dry  hydrogen  chloride  passed  into  the  cold  solution.  The 
white  precipitate  was  washed  with  absolute  ether  and  placed  in 
vacuo  over  concentrated  sulphuric  acid  and  solid  potassium  hy- 
droxide for  forty-five  minutes.  A  sample  of  the  substance  was 
then  dissolved  in  water,  only  a  very  slight  turbidity  appearing, 
the  solution  neutralized  with  sodium  bicarbonate  and  titrated  with 


te.ith-normal  sliver  nitrate,  which  gave  15.60  per  cent.  Cl. ;  calcu- 
lated, 15.49  per  cent. 

Asym.  methy  acetylphenylisourea,  when  treated  with  dry  hy- 
drogen chloride,  at  once  liquefied  and  evolved  methyl  chloride  at 
the  ordinary  temperature. 

About  1.5  grams  of  the  solid  asym.  acylisourea,  not  quite  pure, 
was  placed  in  a  sample  tube  and  kept  for  a  year  and. a  half.  The 
tube  was  then  found  to  contain  an  oil,  near  the  top  of  which  a  few 
plate-like  crystals  (about  o.i  gram)  adhered  to  the  side  of  the 
tube.  The  substance  was  placed  in  a  freezing-mixture  and  cooled 
to  ( — 10°)  for  several  hours,  but  showed  no  tendency  to  solidify 
The  plate-like  crystals  mentioned  above  were  removed,  powdered 
and  washed  with  petroleum  ether.  The  body  melted  at  112°,  even 
when  mixed  with  acetanilide.  No  asym.  acylisourea  could  be 
obtained  from  the  oil  by  treating  it  with  petroleum  ether  accord- 
ing to  the  method  already  pursued  for  the  separation  of  the  two 
isomers.  Some  of  the  oil  was  now  placed  in  a  sample  tube  and 
treated  with  dry  hydrogen  chloride.  Methyl  chloride  began  to  be 
evolved  at  a  temperature  of  60°.  The  solid  residue  was  washed 
with  petroleum  ether  and  the  melting-point  was  found  to  be  183°, 
which  shows  that  the  product  was  sym.  acetylphenylurea.  Hence 
it  is  evident  that  the  asym.  O-methyl  acetylphenylisourea  originally 
placed  in  the  tube  had,  on  being  kept,  passed  over  completely, 
with  the  exception  of  a  small  amount  which  had  decomposed,  into 
the  more  stable  isomeric  sym.  O-methyl  acetylphenylisourea.  The 
rearrangement  can  be  expressed  as  follows : 

CH3CONCflH6.C(OCH3) :  NH  — > 

HNC6H5C(OCH3) :  NCOCH3. 

It  was  found  that  when  the  crystalline  isomer  is  perfectly  pure, 
this  transformation  is  much  slower.  Some  of  the  pure  crystals 
when  kept  several  months  adhered  to  each  other  and  the  melting- 
point  had  fallen  only  7°-io°. 

Action  of  Sodium  Methy  late  and  Silver  Nitrate  on  Asym. 
Methyl  Acetylphenylisourea. — A  solution  of  sodium  methylate 
(from  0.06  gram  sodium  and  3  cc.  pure  methyl  alcohol)  was  added 
to  0.5  gram  asym.  methyl  acetylphenylisourea  (i  mol.)  dissolved 
in  2.5  cc.  methyl  alcohol.  Silver  nitrate,  0.4  gram  (0.8  mol.),  dis- 
solved in  5  cc.  water,  was  gradually  but  rapidly  added  to  the  mix- 


i8 

ture  and  this  thoroughly  shaken  and  cooled  under  the  water  tap. 
The  precipitate,  which  began  to  form  at  once,  was  at  first  brown, 
but  it  quickly  changed  to  a  light  cream  color.  It  was  immediately 
filtered  off,  washed  with  a  mixture  of  methyl  alcohol  and  water 
( i :  i )  until  the  washings  were  no  longer  alkaline  to  sensitive  lit- 
mus paper,  brought  on  a  clay  plate  and  placed  at  once  in  a  vacuum 
desiccator  over  concentrated  sulphuric  acid  and  solid  potassium 
hydroxide.  The  yield  appeared  good.  The  filtrate  when  diluted 
had  a  strong  odor  of  methyl  acetate.  As  soon  as  the  silver  salt 
was  dry,  analyses  were  made.  There  was  found,  41.83,  41.40  and 
41.83  per  cent.  Ag. ;  calculated  for  C10H12O2N2Ag,  41.94  per  cent. 
From  the  analyses  it  is  apparent  that  the  silver  compound  ob- 
tained was  not  the  salt  of  methyl  acetylphenylisourea,  but  the  silver 
salt  of  methyl  phenylisourea  itself,  the  acyl  group  having  been 
saponified  away  by  the  treatment  with  sodium  methylate: 

CH3CONC6H5C( :  NH)OCH3  +  NaO.CH3  +  AgNO3  — * 

CH.COOCH,  +  AgNC(OCH3)NHC6H5  +  NaNO3. 
The  asym.  acylphenylisoureas  are  therefore  saponified  rapidly  and 
smoothly  to  isoureas,  in  marked  contrast  to  their  symmetrical 
isomers. 

The  same  silver  salt  was  now  prepared  directly  from  O-methyl 
phenylisourea. 

Silver  O-Methyl  Phenylisourea,  AgNC(OCHs)NHC6H6  or 
HNC(OCH3)NAgC6H5. — To  a  methyl  alcohol  solution  of  0.5 
gram  methyl  phenylisourea  was  added  a  solution  of  0.45 
gram  (about  0.8  mol.)  silver  nitrate  in  a  mixture  of  water  and 
methyl  alcohol  ( i :  i )  and  then  to  the  whole  was  added,  drop  by 
drop,  with  constant  shaking,  a  concentrated  sodium  methylate 
solution  prepared  from  0.057  gram  (0.75  mol.)  of  sodium.  The 
pure  white  curdy  precipitate  was  filtered  off,  thoroughly  washed 
with  cold  water  until  the  washings  were  no  longer  alkaline,  then 
several  times  with  very  dilute  acetic  acid  to  remove  any  silver 
oxide  and  finally  with  a  little  methyl  alcohol.  The  analysis  gave 
42.08  per  cent.  Ag;  calculated,  41.94  per  cent. 

This  salt  was  also  prepared  in  water  solution  as  follows :  To  a 
saturated  aqueous  solution  of  0.5  gram  methyl  phenylisourea  a 
little  less  than  the  calculated  quantity  of  normal  sodium  hydroxide 
was  added  and  then  the  whole  was  treated  with  somewhat  less  than 


UNIVEK8H 

v       OF 

VP4 


19 

the  theoretical  amount  of  silver  nitrate  in  10  cc.  of  water.  The 
salt  prepared  by  this  method  had  a  yellow  color  and  was  much 
more  difficult  to  purify  than  when  prepared  according  to  the 
method  given  above. 

The  silver  salt  of  methyl  phenylisourea,  0.5  gram,  was  suspended 
in  absolute  ether,  the  whole  well  cooked  and  a  slight  excess  (3 
grams)  acetyl  bromide  added  and  the  mixture  allowed  to 
stand  in  the  dark  for  several  days  with  frequent  shaking.  The 
ether  solution  was  filtered  off  and  evaporated  in  vacuo.  2.5 
grams  of  an  oil  was  left  which,  according  to  the  following  tests, 
consisted  largely  of  sym.  methyl  acetylphenylisourea.  Some  of  the 
oil  was  dissolved  in  absolute  ether  and  treated  with  dry  hydrogen 
chloride.  A  mucilaginous  precipitate  was  filtered  off  and  placed 
in  vacuo  over  night.  This  precipitate,  when  washed  with  absolute 
alcohol  and  dried,  melted  at  183°.  Mixed  with  sym.  acetylphenyl- 
urea,  the  melting-point  was  unchanged. 

The  formation  of  the  sym.  acetyl  derivative  favors  the  following 
as  the  probable  constitution  of  the  silver  salt : 

AgN:C(OCH3)(NHC6H5). 

As  a  rule,  the  metal,  in  the  salts  of  the  phenyl  amidines,  is 
supposed  to  go  to  the  phenylamide  group.1 

Silver  Salt  of  O-Bthyl  Phenylisourea,  HNCQH5C(OC2H6)NAg 
or  C2H5O.C(NH)NAgC6H5.—To  0.5  gram  ethyl  phenylisourea 
in  5  cc.  absolute  ethyl  alcohol  was  added  0.5  gram  (0.9  mol.)  of 
silver  nitrate  dissolved  in  a  mixture  of  water  and  ethyl  alcohol 
( i :  i ) .  The  whole  was  then  treated,  slowly  and  with  constant 
shaking,  with  an  ethyl  alcohol  solution  of  sodium  ethylate  pre- 
pared from  0.06  gram  (0.9  mol.)  of  sodium.  The  curdy  pre- 
cipitate was  filtered  off,  washed,  dried  and  analyzed,  giving  39.88 
per  cent.  Ag;  calculated,  39.80  per  cent. 

Silver  Salt  of  Sym.  Methyl  Acetylphenylisourea. — Sym.  methyl 
acetylphenylisourea,  0.4  gram,  was  nearly  all  dissolved  in  about  12 
cc.  of  water  and  1.8  cc.  (0.85  mol.)  normal  sodium  hydroxide  was 
added  and  then  16  cc.  (0.8  mol.)  tenth-normal  silver  nitrate,  drop 
by  drop,  with  shaking.  The  nearly  white  precipitate  was  filtered  off, 
and  washed  with  water  until  the  washings  were  only  slightly  alka- 
line. An  attempt  was  made  to  wash  with  methyl  alcohol,  but  the 

1  Bamberger  :  Loc.  cit. 


20 

first  drop  dissolved  some  of  the  precipitate  and  no  more  was  added. 
The  washing  was  completed  with  ether  and  the  salt  dried  in  the 
usual  way.  The  analysis  gave  35.72  per  cent.  Ag;  calculated  for 
C10H12O2N2Ag,  36.06  per  cent. 

O-Methyl  Acetylisourea,  CHsCONC(OCH3)NH2.—Methylis<>- 
urea  hydrochloride,  2  grams,  and  about  15  cc.  absolute  ether  were 
placed  in  a  flask,  2  grams  (2  mols.)  potassium  hydroxide  in  I  cc. 
water  were  added,  the  mixture  shaken  and  the  whole  cooled  to  o°. 
Two  grams  (i  mol.)  acetic  anhydride  were  now  added  and  the 
mixture  shaken  for  some  time.  The  ether  solution  was  poured 
off,  the  residue  extracted  again  with  ether  and  nearly  the  whole 
of  the  latter  allowed  to  evaporate  in  the  air.  The  extract  was  then 
placed  in  a  vacuum  desiccator  for  an  hour  or  two.  The  substance, 
which  was  at  first  oily,  became  solid.  It  was  purified  by  recrystal- 
lization  from  warm  petroleum  ether.  After  one  recrystallization 
the  melting-point  was  constant  at  58.5°.  The  analysis  gave  23.94 
per  cent.  N. ;  calculated,  24.19  per  cent. 

Silver  Salt  of  O-Methyl  Acetylisourea, 

CH,C(OAg) :  NC(OCHZ) :  NH. 

— Methyl  acetylisourea,  1.5  grams,  was  dissolved  in  about  8  cc. 
absolute  methyl  alcohol  and  a  concentrated  methyl  alcohol 
solution  of  sodium  methylate  (0.8  mol.)  was  added  and  the  whole 
treated  with  1.3  grams  silver  nitrate.  The  white  gelatinous  pre- 
cipitate was  washed  as  thoroughly  as  possible  until  the  washings 
were  only  very  slightly  alkaline.  The  yield  was  good.  There 
was  found,  on  analysis,  48.14  per  cent.  Ag;  calculated,  48.35  per 
cent. 

O -Methyl  m-Nitrobenzoylisourea, 

m-N02CQH,CONC(NH2)  OCH3. 

— Methyl  isourea  hydrochloride,  3  grams,  was  dissolved  in  about 
20  cc.  water  and  3  grams  (2  mols.)  potassium  hydroxide  dissolved 
in  a  little  water  were  added  and  then  5.1  grams  (i  mol.)  w-nitro- 
benzoyl  chloride  and  the  whole  thoroughly  shaken.  A  colorless 
solid  separated  out.  The  yield  was  almost  quantitative.  The 
substance  was  dissolved  in  benzene  or  in  chloroform  and  repre- 
cipitated  by  petroleum  ether.  In  this  way  it  was  obtained  in  the 
form  of  fine  needles  melting  at  115°.  These  gave  19.00  per  cent. 
N. ;  calculated,  18.87  Per  cent- 


21 
II.      CONDENSATIONS  OF  THE  ISOUREAS. 

Sym.  0-Methyl  Diphenyldiureidoisourea, 

CQH5NHCONHC(OCH3) :  NCONHC6H6. 

— Methyl  phenylisobiuret,  0.6  gram,  prepared  according  to  the 
method  of  Stieglitz  and  McKee,  was  treated  with  0.3  gram  phenyl- 
isocyanate,  the  material  being  kept  cold.  The  product  soon  be- 
came semi-fluid  and  after  standing  over  night  the  contents  of  the 
tube  had  become  solid.  This  solid  was  washed  a  great  many  times 
with  ether  and  then  melted  constant  at  153°.  It  gave:  C,  61.60; 
H,  5.46.  Calculated:  C,  61.47;  H,  5.18. 

Some  of  the  above  compound  was  dissolved  in  absolute  ether 
and  treated  with  a  little  dry  hydrogen  chloride.  The  precipitate 
was  filtered  off,  washed  with  absolute  ether  and  dried  as  usual  for 
one  and  a  half  hours.  The  salt  melted  at  122°,  giving  off  methyl 
chloride.  A  chlorine  determination  gave  results  agreeing  best 
with  a  sesquichloride.  There  was  found  14.81  per  cent.  Cl.  Cal- 
culated for  (C16H16O3N4)2.3HC1,  14.48  per  cent. 

Carbonyl  Diphenyldiurea,  (C6H5NHCONH)2CO.—$ome  of 
the  diureid  was  placed  in  a  sample  tube  and  treated  with  dry  hy- 
drogen chloride  at  60°.  Methyl  chloride  was  evolved  and  a  color- 
less solid  was  left  which  melted  sharply  at  211°.  As  the  quantity 
was  small,  the  substance  was  placed  in  a  desiccator  for  a  day  or 
two  and  then  analyzed  without  further  purification.  It  gave: 
C,  60.50;  H,  5.20.  Calculated:  C,  60.34;  H,  4.74. 

O-M ethyl  Carbethoxyisourea,  C2H5OCONC  ( O  CH3 )  NH2.— 
Methyl  isourea  hydrochloride,  2  grams,  was  treated  at  o°,  in 
ethereal  solution  with  potassium  hydroxide  (2.2  grams  dissolved 
in  1.5  cc.  water)  and  ethyl  chlorformate  (1.9  gram).  The  dried 
ether  extracts  left  a  colorless  mobile  oil,  which,  when  it  was 
cooled  in  a  freezing-mixture  and  persistently  scratched,  solidified 
completely.  The  substance  was  purified  by  precipitation  from 
ether  solution  by  petroleum  ether.  The  melting-point  is  5°.  The 
analysis  gave:  C,  41.15;  H,  7.21.  Calculated:  C,  41.05;  H,  6.91. 

O-M  ethyl  Carbethoxyisourea  Hydrochloride, 

C2H5OCONC(OCHS)NH2.HCI. 

— Some  methyl  carbethoxyisourea  was  dissolved  in  absolute  ether 
and  dry  hydrogen  chloride  passed  into  the  solution.  The  precipi- 
tate was  filtered  off,  washed  and  dried  as  usual  and  analyzed 


22 

(I,  II  and  III)  after  an  interval  of  half  an  hour  and  again  (IV) 
after  a  week.  There  was  found,  I,  17.72,  II,  18.02,  III,  19.16, 
and  IV,  15.15  per  cent.  Cl.  Calculated,  19.40  per  cent. 

These  results  show  a  gradual  decomposition  with  loss  of  chlo- 
rine.    The  decomposition  occurs  as  follows: 
C2H5OCONC(OCH3)NH2.HCl-~ 

CH3C1  +  C2H5OCONHCONH2. 

This  was  confirmed  by  the  following:  Some  methyl  carbethoxy- 
isourea  was  treated  with  dry  hydrogen  chloride;  at  the  ordinary 
temperature,  methyl  chloride  was  evolved.  The  solid  residue  was 
washed  with  water  and  dried;  it  then  melted  at  191°  and  was 
recognized  as  allophanic  ester. 

Some  of  the  hydrochloride,  when  heated,  evolved  methyl  chlo- 
ride in  quantity  at  90°. 

All  attempts  to  introduce  a  second  carbethoxyl  group  left  the 
body  unchanged. 

0  -Methyl  Thiophenylureidoisourea, 

(C6H5NHCSN:)C(OCH3)NH2. 

— Methyl  isourea,  0.2  gram,  was  mixed  with  0.5  gram  phenyl 
mustard  oil;  heat  was  evolved  and  the  product  soon  solidified 
when  it  was  cooled.  The  substance  was  purified  by  several  re- 
crystallizations  from  hot  benzene.  Obtained  thus,  the  compound 
consists  of  diamond-shaped  plates,  insoluble  in  water  and  ether 
but  easily  soluble  in  chloroform.  The  melting-point  is  131°. 

The  compound  can  also  be  obtained  much  more  conveniently  by 
warming  the  isourea  hydrochloride  with  phenyl  mustard  oil  and 
potassium  hydroxide  in  the  presence  of  a  little  water.  The  yield, 
however,  is  much  less  by  this  method. 

The  substance  is  somewhat  unstable.  When  kept  in  a  desiccator 
several  days  it  melted  at  I2i°-i26°  and  on  analysis  (I)  gave  a  low 
nitrogen  content.  Another  sample  (II)  was  analyzed  after  re- 
maining in  a  vacuum  only  two  hours.  The  results  were  19.04 
and  19.92  per  cent.  N.  Calculated,  20.13  per  cent. 

Methyl  phenylisothiobiuret  was  dissolved  in  chloroform  and 
dry  hydrogen  chloride  added.  The  white  crystalline  precipitate 
was  dried  and  when  heated  to  115°  melted  with  evolution  of 
methyl  chloride. 

Methyl  phenylisothiobiuret,  when  treated  with  dry  hydrogen 
chloride  and  heated  to  75°-9O°,  gave  off  methyl  chloride.  The 


23 

solid  phenylthiobiuret  remaining  in  the  tube  was  recrystallizcd 
from  absolute  alcohol  and  obtained  in  the  form  of  very  fine 
needles,  which  melted  at  171°  with  decomposition,  a  gas  being 
evolved  having  an  odor  similar  to  that  of  mercaptan. 

While  methyl  isourea  condenses  with  2  molecules  of  phenyliso- 
cyanate,  it  reacts  only  with  I  molecule  of  phenyl  mustard  oil. 

O-M ethyl  Isobiuret,  H2NCON :C(OCH3)NH2.— One  gram 
methyl  isourea  hydrochloride  was  dissolved  in  4  cc.  water  and 
added  to  a  solution  of  0.08  gram  potassium  isocyanate  in  4  cc. 
water  and  the  mixture  allowed  to  evaporate  to  dryness  in  a  warm 
place.  The  residue  was  extracted  repeatedly  with  boiling  benzene. 
The  benzene  solution  was  evaporated  and  0.2  gram  of  a  solid  was 
obtained  which  melted  at  110°.  Some  of  this  solid,  when  treated 
with  dry  hydrogen  chloride,  began  to  evolve  methyl  chloride  at  the 
room  temperature  and  left  a  product  which,  thoroughly  washed 
with  water  and  dried,  melted  at  190° — the  melting-point  of 
biuret.  It  also  gave  the  biuret  reaction  with  copper  sulphate  and 
sodium  hydroxide.  Methyl  isobiuret,  when  purified  by  recrystal- 
lization  from  hot  benzene,  melted  at  118°. 

The  analysis  gave :  C,  30.98 ;  H,  6.30.  Calculated :  C,  30.72 ;  H, 
6.03. 

Benzylidene  Dimethyldiisourea, 

CQH5CH:(NHC(OCH3)  :NH)2. 

— Methyl  isourea,  0.72  gram,  was  added  to  I  gram  (a  mol.)  benz- 
aldehyde.  Nearly  all  the  methyl  isourea  dissolved  in  a  few  minutes 
without  heat  evolution.  After  standing  for  about  two  days,  the  sub- 
stance was  almost  completely  solid.  This  solid,  insoluble  in  ether, 
acetone  and  chloroform  but  soluble  in  methyl  alcohol,  was  washed 
many  times  with  absolute  ether.  It  then  melted  constant  at  137°. 
The  ether  washings  were  treated  with  dry  hydrogen  chloride  and 
allowed  to  stand  and  a  small  amount  of  a  crystalline  substance 
separated  which  melted  at  235°.  Tribenzotetraureid  melts  at 
240°. 

The  substance  melting  at  137°  was  analyzed  and  gave:  C, 
55.33 ;  H,  6.81.  Calculated :  C,  55.85 ;  H,  6.84. 

It  is  evident  from  the  above  that  2  molecules  of  methyl  isourea 
reacted  with  one  of  the  benzaldehyde  as  follows : 

2H2NC(OCH3)  :  NH  +  C6H5CHO— 

C,H5CH  :  [NHC(OCH3)  :  NH]2  +  H2O. 


24 

Small  quantities  of  a  tribenzylidene  tetraisourea  were  formed 
at  the  same  time. 

Some  of  the  diisourea  when  treated  with  dry  hydrogen  chloride 
evolved  methyl  chloride  at  the  room  temperature.  The  residue, 
benzylidene  diureid,  was  washed  with  ether  and  acetone  and  began 
to  decompose  when  heated  to  195° -200°  and  melted  at  210°, 
giving  off  a  little  gas.  Schiff1  gives  the  melting-point  of  his 
benzodiureid  as  195°  and  adds  that  heated  higher  it  decomposed. 
Richter  gives  the  melting-point  200°. 

The  following  experiment  was  made  in  the  attempt  to  obtain 
the  hydrochloride.  The  isodiure'id  was  dissolved  in  absolute 
methyl  alcohol  and  dry  hydrogen  chloride  slowly  passed  into  the 
cold  solution.  A  precipitate,  obtained  by  the  addition  of  ether, 
was  filtered  off,  washed  and  dried  as  usual  for  two  hours. 

It  then  melted  at  85°,  giving  off  methyl  chloride.  It  gave,  by 
titration,  19.37  Per  cent-  Cl.  Calculated  for  CnH16O2N4.2HCl, 
22.91  per  cent. 

Benzylidene  Diethyldiisourea, 

CQH5CH:  [NHC(OC2H5):NH]2. 

— Ethyl  isourea,  0.7  gram,  dissolved  in  a  little  absolute  ether,  was 
mixed  with  0.84  gram  (i  mol.)  redistilled  benzaldehyde.  After 
standing  two  weeks,  a  white  crystalline  mass  was  obtained  which 
was  thoroughly  washed  many  times  with  absolute  ether  and  finally 
with  a  little  acetone.  The  substance  then  melted  at  154°  and  was 
insoluble  in  water,  ether  and  alkalies  and  nearly  insoluble  in  ben- 
zene, but  soluble  in  chloroform,  acetone  and  in  dilute  acids.  No 
definite  crystalline  form  could  be  observed  under  the  microscope. 

The  analysis  gave:  C,  59.19;  H,  7.51.  Calculated:  C,  59.01; 
H,  7.64. 

An  impure  hydrochloride  of  the  isodiureid  was  obtained  by 
treating  a  chloroform  solution  of  the  ureid  with  dry  hydrogen 
chloride.  When  heated,  this  salt  melted  and  gave  off  ethyl  chlo- 
ride at  90°.  The  chloride  was  allowed  to  stand  in  the  air  in  a 
warm  place  for  several  hours.  The  melting-point  was  then  found 
to  be  195° — the  melting-point  of  benzodiureid.  Evidently  com- 
plete decomposition  had  occurred. 

Some  ethyl  isourea  and  benzaldehyde  were  mixed  in  equimolec- 
ular  quantities  and  the  mixture  allowed  to  stand  for  several 

i  Ann.  Chem.  (Uebig),  151.  J92  (1869). 


25 

months.  The  product  was  then  washed  with  ether  and  treated 
with  dry  hydrogen  chloride.  Ethyl  chloride  was  evolved  and  a 
solid  residue  remained  which,  when  purified,  melted  at  240°  with 
decomposition.  This  is  the  melting-point  tribenzylidene  tetra- 
ureid.  Evidently  the  substance  formed  by  the  long-continued 
action  of  benzaldehyde  was  a  much  higher  condensation  product 
than  that  first  obtained.  This  substance,  as  is  shown  by  its  de- 
composition product,  tribenzylidene  tetraureid,  was  tribenzylidene 
tetrethyl  isotetraure'id. 

By  condensation  of  isourea  ethers  with  /3-keto-acid  esters  the 
oxygen  ethers  of  ju  -oxypyrimidines  were  easily  obtained.  Their 
ready  formation  by  this  method  promises  to  be  serviceable  in  syn- 
thetic work  in  the  uric  acid  series.1 

IJL-Methoxy-a-methyl-y-oxypyrimidine, 

N:  C(OCH^N:  C(CH,}CH:  C  OH. 


— A  mixture  of  0.5  gram  methyl  isourea  and  0.8  gram  (i  mol.) 
acetoacetic  ether  formed  a  light  yellow  oil  which,  after  standing 
a  day  or  two^or  upon  being  warmed  on  the  water-bath  to  50° 
for  a  few  minutes,  almost  completely  solidified.  The  product 
was  thoroughly  washed  with  ether  and  crystallized  from  boiling 
alcohol  in  feathery  masses  of  needles  which  melted  constantly  at 
207°  after  several  recrystallizations.  The  yield  was  about  90  per 
cent,  of  the  theoretical.  The  pyrimidine  is  insoluble  in  the  or- 
dinary organic  solvents  in  the  cold,  readily  soluble  in  boiling  ben- 
zene or  alcohol,  as  well  as  in  dilute  acids  or  alkalies.  • 

The  analysis  gave:  C,  51.26;  H,  5.93.     Calculated:  C,  51.37; 

H,  576. 

The  reaction  between  methyl  isourea  and  acetoacetic  ether  is 
analogous  to  that  between  the  amidines  and  acetoacetic  ether,2  and 
may  be  given  as  follows : 
CH3OC(  :  NH)NH2+  CH3C(OH)  :  CHCOOC2H5-> 

N  :C(OCH3)N  :  C(CH3)CH  :  C(OH)  +  C2H6O  +  H2O 
I I 

The  splitting  off  of  both  alcohol  and  water  seems  to  be  simul- 
taneous, as  no  indications  of  any  intermediate  products  were  ever 
found. 
A  little  of  the  oxypyrimidine  was  dissolved  in  the  minimum 

1  Mr.  R.  W.  Noble  is  carrying  out  work  along  this  line  in  this  laboratory.— J.  S. 

2  pinner:  "  Imidoather,"  p.  216. 


26 

amount  of  ethyl  alcohol  and  treated  with  a  slight  excess  of  hydro- 
chlorplatinic  acid,  also  in  concentrated  solution.  Absolute  ether 
was  now  added  and  an  oil  was  precipitated,  which  soon  crystal- 
lized in  the  form  of  yellow  spindle-shaped  needles.  The  crystals 
were  dried  for  half  an  hour,  and  then  gave  28.33  Per  cent-  Pt. 
Calculated  for  (C6H8O2N2)2H2PtCl6,  28.24  per  cent. 

A  small  amount  of  the  oxypyrimidine  was  dissolved  in  dry 
benzene  and  treated  with  dry  hydrogen  chloride.  The  precipitate 
was  dried  in  vacuo  over  solid  potassium  hydroxide  for  half  an 
hour. 

Some  of  the  hydrochloride  evolved  methyl  chloride  when  heated 
to  90° -i 00°.  The  solid  residue  began  to  decompose  when  heated 
to  270°,  proving  it  to  be  methyl  uracil — formed  according  to 

HC1,  N  :  C(OCH3)N  :  C(CH3)CH  :  COH— 

I i 

HN,  CO.N  :  C(CH3)CH  :  COH  +  CH3C1 

By  titration  there  was  found  20.03  Per  cent-  Cl.  Calculated, 
20.06  per  cent. 

The  silver  salt  was  obtained  from  0.2  gram  of  the  oxypyr- 
imidine dissolved  in  absolute  methyl  alcohol,  by  the  addition  of 
a  methyl  alcohol  solution  of  sodium  methylate  (prepared  from 
the  calculated  amount  of  sodium)  and  then  of  the  equivalent 
amount  of  silver  nitrate  in  a  mixture  of  methyl  alcohol  and  water 
( i :  i ) .  A  very  thick  gelatinous  precipitate  formed  which  it  was 
impossible  to  wash  even  with  the  pump.  It  was  placed  on  a  clay 
plate  in  vacuo  for  several  days  until  it  was  perfectly  dry,  then 
finely  powdered  and  washed  repeatedly  with  water,  methyl  alcohol 
and  ether,  and  dried  as  before.  It  thus  gave  43.36  per  cent.  Ag. 
Calculated  for  C6H7O2N2Ag,  43.65  per  cent. 

p-Ethoxy-  a-methyl-  y-oxypyrimidine, 

N:  C(OC,H,).N:  C(CHZ)CH :  COH 

— Ethyl  isourea,  2  grams,  was  mixed  with  3  grams  (i  mol.)  aceto- 
acetic  ether.  The  mixture,  warmed  at  60°  for  one  hour,  almost 
completely  solidified.  This  solid,  when  washed  with  absolute 
ether  and  recrystallized  from  boiling  absolute  alcohol,  was  ob- 
tained in  the  form  of  fine  shining  needles,  which  melted  at  206°. 
These  gave :  C,  54.43 ;  H,  6.73.  Calculated :  C,  54.48 ;  H,  6.55. 


27 

The  chlorplatinate  was  prepared  by  the  method  described  above 
for  the  corresponding  methyl  derivative.  The  crystals  were  yel- 
low needles,  which  gave  26.95  per  cent.  Pt.  Calculated,  27.14 
per  cent. 

A  small  amount  of  the  oxypyrimidine  in  concentrated  benzene 
solution  was  treated  with  a  little  dry  hydrogen  chloride.  The 
precipitate  was  washed  with  dry  benzene  and  dried  for  forty 
minutes  (I)  and  eighteen  hours  (II),  respectively.  By  titra- 
tion  these  gave,  1749  and  17.78  per  cent.  Cl.  Calculated  for 
C7H10O2N2HC1,  18.59  per  cent. 

Some  of  the  oxypyrimidine  was  heated  in  a  stream  of  dry 
hydrogen  chloride  and  evolved  ethyl  chloride  at  9O°-I3O°.  The 
solid  residue  decomposed  when  heated  to  270°.  It  was  methyl 
uracil. 

fJi-Methoxy-  a-methyl-$-ethyl-  y '-oxypyrimidine, 

N:  C(  OCH,}  .N:  C.  ( C7/3) .  C(  C,//6)  C  OH. 


— Methyl  isourea,  0.6  gram,  was  mixed  with  1.2  grams  (i  mol.) 
ethyl  acetoacetic  ether.  The  mixture  formed  a  clear  oil  which 
on  standing  over  night  became  filled  with  four-sided  needles  in 
masses  from  a  common  center.  The  crystals  were  washed  with 
absolute  ether  and  after  several  recrystallizations  from  hot  abso- 
lute alcohol  melted  constant  at  210°. 

The  compound  is  easily  soluble  in  acid  or  alkali.  The  analysis 
gave:  C,  56.94;  H,  7.43.  Calculated:  C,  57.07;  H,  7.20. 

An  attempt  was  made  to  prepare  the  hydrochloride  from  the 
oxypyrimidine  in  benzene  or  chloroform  solution  and  dry  hydrogen 
chloride,  but  the  product  was  always  mucilaginous  and  not  easily 
purified.  However,  the  salt  was  easily  obtained  from  a  solution 
of  0.3  gram  oxypyrimidine  in  the  calculated  amount  of  hexanor- 
mal  hydrochloric  acid,  by  evaporation  in  vacuo.  After  standing 
in  vacuo  nearly  a  day  the  dry  salt  was  analyzed,  and  gave  17.12  per 
cent.  Cl.  Calculated  for  C8H13O2N2C1,  17.31  per  cent. 

O-M ethyl  Oxdylisourea,  (  p-M  ethyl  Parabanic  Acid), 

NH.  C(  OCH^ :  N.  CO.  CO. 

i I 

— Methyl  isourea,  0.4  gram,  was  mixed  with  a  slight  excess  (i 
gram)  oxalic  ester.  In  a  few  minutes  the  whole  mass  apparently 
became  solid.  After  standing  for  several  days,  the  compound 


28 

was  washed  repeatedly  with  ether,  benzene  and  petroleum  ether 
and  then  recrystallized  from  absolute  alcohol.  It  was  obtained 
in  the  form  of  three-sided  prisms,  which  melt  at  137.5°.  The 
crystals  are  insoluble  in  ordinary  organic  solvents,  but  easily 
soluble  in  water,  alkali  and  boiling  alcohol. 

The  chlorplatinate  of  this  substance  was  prepared  and  analyzed 
as  follows:  A  small  amount  of  the  compound  was  dissolved  in 
absolute  alcohol  and  about  the  calculated  quantity  of  hydrochlor- 
platinic  acid,  also  in  absolute  alcohol,  was  added.  Upon  the  ad- 
dition of  dry  benzene,  a  bright  yellow  solid  separated. 

This  gave  29.60  per  cenr.  Pt.  Calculated  for  C8H10O6N4PtCl0, 
29.71  per  cent. 

The  reaction  by  which  methyl  oxalylisourea  is  formed  may  be 
given  as  follows : 

CH3OC(  :  NH)NH2  +  (COOC2H5)2~ 

CH3OC  :  N.CO.CONH  -f-  2C2H6O 

[ i 

Some  of  the  compound,  when  treated  with  a  little  dilute  hydro- 
chloric acid,  dissolved  completely  at  first  and  then  almost  imme- 
diately deposited  a  solid.  This  solid,  dried  in  vacuo,  was  gently 
heated,  dissolved  in  alcohol  and  reprecipitated  by  petroleum  ether. 
The  substance  thus  obtained  began  to  decompose  when  heated 
to  190°.  It  was  undoubtedly  oxalylurea. 

in.    THE  AFFINITY  CONSTANTS  OF  ISOUREAS. 
For  an  isourea  which  is  ionized  according  to   4 

HN  :  C(OR)NH2,  H2COHN  :  C(OR)NH3  +  OH, 
and  which  does  not  belong  to  the  class  of  strongest  bases,1  such 
as  the  alkalies,  we  would  have  the  affinity  constant,  K,  expressed 
in  the  following  equation: 

CoHXCp  =  KXCM.  (i) 

COH  and  CP  are  the  concentrations  of  the  hydroxyl  ions  and 
the  positive  base  ions  in  terms  of  gram  ions  per  liter  and  C«  is 
the  concentration  of  the  non-ionized  amine. 

The  affinity  constants  of  the  most  important  representatives  of 

1  For  the  strongest  bases,  as  is  well  known,  equation  (\)  does  not  hold  good.  Vide 
Rudolphi :  Ztschr.  phys.  Chem.,  17,  385;  Van't  Hoff:  Ibid.,  18,  301  ;  Kohlrausch :  Ibid.,  18, 
661.  The  isomers,  as  will  be  shown  below,  give  good  constants  according  to  (i)  and  be- 
long, therefore,  to  the  so-called  class  of  "half  electrolytes."  (Van't  Hoff:  "Theoretical 
and  Physical  Chemistry,"  I,  p.  117.) 


29 

the  typical  classes  of  isoureas,  H2NC(OR):NH,  and  (alphyl) 
HNC(OR)  :  NH,  were  determined  by  the  conductivity  method 
as  developed  by  Ostwald,1  and  van't  HofP  and  as  applied  espe- 
cially by  Bredig3  to  the  measurement  of  the  affinity  constants  of 
bases.  The  proportion  (or)  of  the  base  ionized  in  a  given  solu- 
tion was  ascertained  from  the  molecular  conductivity  of  the  solu- 
tion from  the  relation 


in  which  A*>  expresses  the  molecular  conductivity  of  the  base 
when  i  gram-molecule  is  dissolved  in  v  cc.  water,  and  Aw  *s  the 
extreme  molecular  conductivity. 

Then  if  we  express  by  A  the  number  of  liters4  containing  I 
gram-molecule  of  the  amine,  equation  (I)  resolves  itself  into 

(3)' 


The  molecular  conductivities  A»  of  the  bases  were  determined 
by  conductivity  measurements  made  with  solutions  of  the  free 
bases.  The  Kohlrausch  apparatus  was  used  and  the  measure- 
ments made  at  a  temperature  of  25°  (±0.01°).  The  molecular 
conductivities  of  the  bases  in  the  extreme  dilution,  A«,I  were 
ascertained  in  the  usual  way  by  a  determination  of  the  extreme 
molecular  conductivity,  A'OO>  °f  the  hydrochlorides  of  the  bases  — 
and  by  calculation  of  A*,  according  to  the  well-known  equation, 
Aoo  —  A'OO  —  4>ci  +  4>OH  (4) 

in  which  AOO  and  A'OO  are  the  extreme  molecular  conductivities 
of  the  free  bases  and  the  hydrochlorides  respectively  and  /^QH 
and  /ooci  represent  the  extreme  mobility  of  the  hydroxyl  and  the 
chlorine  ions.  /^OH  was  taken  as  I95.8,6  /«,ci  as  75.  9,  7  both  in 

1  Ztschr.  phys.  Chem.,  2,  36,  270  (1888). 

2  Ibid.,  2,  781  (1888). 
a  Ibid.,  13,  289  (1893). 

*  The  conductivity  measurements  are  given  in  this  paper  in  reciprocal  ohms,  and  all 
the  units  used  in  the  measurements  are  those  given  in  Kohlrausch  and  Holborn's 
"  I<eitverm6gen  der  Blektrolyte,"  the  unit  of  concentration  being  the  gram-molecule  (or 
equivalent)  in  i  cc.  The  affinity  constants,  however,  are  given,  in  accordance  with  the 
more  general  usage,  in  terms  of  the  unit  of  concentration  of  i  gram-molecule  per  liter. 

5  Ostwald  :  Ztschr.  phys.  Chem.,  2,  278  (1889). 

6  Kohlrausch  (Loc.  cit.,  p.  200)  gives  for  /^OH  at  18°  the  value  174  in  reciprocal  ohms. 
Its  value  at  25°  was  calculated  with  the  aid  of  the  temperature  coefficient  (a)  for  hydroxyl 
ions  as  determined  by  I<oeb  and  Nernst  (Ztschr.  phys.   Chem.,  2,  963).    a  =  0.0159  and 

is  =  4s  !>+«(<  —  25)]- 

7  Kohlrausch  (Loc.  cit.)  gives  for  the  extreme  mobility  of  chlorine  ions  at  18°  the  value 
65.9.    The  temperature  coefficient  for  these  ions  is  0.022  of  the  value  found  at  18°  (Arrhe- 
nius  :  "  Electrochemistry,"  p.  142). 


30 

reciprocal  ohms,  for  25°.  By  combining  (2),  (3)  and  (4)  the 
constants,  K,  were  calculated  on  the  basis  of  the  experimental 
determinations  made.  The  results  obtained  with  the  various  bases 
follow : 

Methyl  Isourea,  HN  :C(OCH3)NH2.— Methyl  isourea  chloride, 
prepared  according  to  the  method  of  Stieglitz  and  McKee,1  and 
recrystallized  twice  from  boiling  absolute  methyl  alcohol,  washed 
with  absolute  ether  and  placed  in  vacuo  over  solid  potassium  hy- 
droxide and  concentrated  sulphuric  acid  for  three  days.  A  solu- 
tion of  some  of  this  salt  in  water  reacted  neutral  to  sensitive  litmus 
paper.  An  analysis  gave  32.22  per  cent.  Cl.  Calculated  for 
C2H6ON2.HC1,  32.04. 

The  conductirity  measurements  with  this  salt  are  given  in 
Table  I,  in  which  v  is  the  volume  in  liters,  containing  a  gram- 
molecule  of  the  salt,  A»  the  molecular  conductivity  at  25°  in  re- 
ciprocal ohms,  at  the  concentration  in  question.  A'«>  > the  extreme 
molecular  conductivity  of  the  salt,  is  found  according  to  Ost- 
wald's2  and  Bredig's3  empirical  law  from  each  molecular  conduc- 
tivity, Av  »  by  adding  values,4  dv,  which  are  characteristic  for  the 
differences  A«,  — At/,  and  which  are  approximately  constant  for 
salts  in  general. 

TABI,E  I. 

v.  A».  A'o,- 

i.  n.  i.  ii. 

32  104.06         104.04  119.1          119.0 

64  107.97         107.97  119.7          119.7 

128  111.30          110.98  IJ9-9          119.6 

256  US-IS          113-05  II9-55        II9-7 

512  U5.87  H5.5I  120.2  119.8 

1024  [120.12]       [118.17]  [I23-3]       [121.4] 

Means  (excluding  v=  1024):         119.7          119.6 

In  taking  the  mean  value  for  A'*,*  the  value  found  when 
v  =  1024,  was  excluded  because  of  the  obvious  fact  that  at  that 
dilution  some  irregularity  manifests  itself.  The  irregularity  is 
either  due  to  a  slight  hydrolysis  or,  much  more  likely,  to  the  fact 

1  Loc.  cit. 

2  "  L,ehrbuch  d.  Allgem.  Chemie,"  Vol.  II,  693. 
8  Ztschr.  phys.  Chem.,  13,  198. 

4  Bredig's  values  for  dv  were  used,  multiplied  by  the  factor  i. 066  to  convert  the  re- 
ciprocal Siemens'  units  into  reciprocal  ohms  (see  Kohlrausch :  Loc.  cit.,  p.  144,  for  the 
use  of  the  factor  1.066  in  place  of  1.063,  the  international  factor). 


lliat  at  that  dilution  methyl  isourea  begins  to  act  perceptibly  as  a 
diacid  base.1 

The  agreement  between  the  values  for  A'     in  each  series  and 

A\.    00 

between  the  means  for  each  series  is  very  satisfactory.  This 
fact  shows  that,  except  possibly  in  very  high  dilutions  (when 
v  =  1024)  and  probably  not  even  then,  there  is  no  hydrolysis  of 
the  salt  of  any  moment.  Even  the  most  dilute  solutions  were  per- 
fectly neutral  to  sensitive  litmus  paper  and  litmus  solution. 

Since  ^01=75.9  at  25°  we  have  /ooP  =  119.7  —  75-9  =  43-8. 
That  is,  the  extreme  mobility  of  the  positive  ion  of  methyl  isourea 
is  43-8. 

The  molecular  conductivity  of  the  free  base  in  extreme  dilu- 
tion, A  oo>  is  found  from  equation  (4). 

A*,  =  /OOP  +  /OOOH  =  43-8  +  195-8  =  239.6. 

A  sample  of  the  free  base  was  prepared  according  to  the 
method  of  Stieglitz  and  McKee,2  and  dried  next  to  solid  potas- 
sium hydroxide  for  several  hours.  Its  purity  was  ascertained  by 
titration  against  tenth-normal  hydrochloric  acid  (with  methyl 
orange  as  indicator).3 

0.0939  gram  required  12.68  cc.  tenth-normal  HC1.  Calculated, 
12.66  cc. 

The  conductivity  measurements  for  the  free  base  at  25°  are 
given  in  Table  II,  in  which  v  and  A*/  have  the  same  meanings  as 
in  Table  I.  In  the  third  column  the  values  for  a  are  given  as 
calculated  according  to  equation  (2),  and  in  the  last  column 

TABLE  II. 


V, 

Az>. 

looa.            io6K. 

i. 

n. 

I. 

ii. 

i. 

ii. 

C 

10.61 
14.60 

10.57 
14.59 

4-43 
6.  10 

4-42 
6.10 

6.4 
6.4 

6.4 

6.2 

128 

20.30 

20.22 

8.48 

8-45 

6.1 

6,1 

256 

27-73 

27.57 

11-55 

11.52 

5-9 

5-9 

5" 

37-93 

37-02 

15-85 

15-47 

5-8 

5-5 

1024 

51-74 

49-35 

21.62 

20.62 

5-9 

5-2 

Means :  6.08      5.90 

1  Vide,  Bredig :  Loc.  ctt.,  p.  122.  For  the  case  in  question,  the  correctness  of  this 
latter  view  is  demonstrated  by  the  fact  that  the  weaker  bases  of  the  series,  the  phenyl- 
isoureas,  do  not  show  any  anomaly  ;  their  salts  would  be  much  more  likely  to  suffer  hy- 
drolysis than  the  salts  of  the  unsubstituted  isoureas,  but  they  would  be  much  less  likely 
to  behave  as  diacid  bases.  Their  normal  behavior  is  good  evidence,  therefore,  that  the 
irregularity  in  the  case  of  methyl  and  ethyl  isourea  when  v  is  1024  is  due  to  the  partial 
ionization  of  the  latter  as  diacid  bases. 

»  Loc.  ctt. 

«  Stieglitz  and  McKee :  Loc.  cit. 


32 

the  values  for  the  affinity  constant,  K,  are  given  as  determined 
from  equation  (3). 

For  comparison,  the  affinity  constant  of  urea  was  calculated 
from  the  data  given  by  Walker1  on  the  hydrolysis  of  solutions 
of  urea  hydrochloride  containing  varying  proportions  of  the  acid 
and  base.  The  constant,  K,  was  derived  according  to  Walker's 
formula 

Salt         ^ 
Acid  X  Base 

in  which  salt,  acid  and  base  represent  the  concentrations  of  the 
substances  in  gram-molecules  per  liter.  The  average  constant 
was  found  to  be  1.28  (±0.06).  This  constant,  according  to 
Arrhenius2  is  the  constant  ratio  between  the  affinity  constant  of 
the  base  and  the  dissociation  constant  of  water  which  is 
i.2X  io~~14.  We  find  thus  the  affinity  constant3  of  urea  to  be 
1.28  X  1.2  X  io~14  or  1.54  X  io~14.  Urea  is  then  but  little 
stronger  as  a  base  than  water — namely,  about  sixty  times  as 
strong.4  The  simplest  isourea,  methyl  isourea,  whose  affinity  con- 
stant, as  just  determined,  is  6.4  X  io~5  ,  is,  therefore,  4  X  io9 
as  strong  a  base  as  the  parent  substance,  urea. 

It  is  a  base  whose  affinity  is  of  the  order  of  that  of  ammoniar> 
(KNH4oH  =  i.8X  io-5). 

Guanidine,  the  amide  corresponding  to  the  isourea  ethers,  is 
a  very  much  stronger  base,  standing  much  closer  to  the  alkalies 
than  to  the  amines.6 

Ethyl  Isourea,  NH2C(OC2H5)  :NH.— Ethyl  isourea  hydrochlo- 
ride was  recrystallized  twice  from  boiling  absolute  alcohol.  An 
aqueous  solution  of  the  salt  was  neutral  to  sensitive  litmus  paper. 
The  salt  was  dried  for  three  days  over  concentrated  sulphuric 
acid  and  solid  potassium  hydroxide,  and  its  purity  tested  by  a 
titration  against  tenth-normal  silver  nitrate,  which  gave  28.61  per 
cent.  Cl.  Calculated  for  C3H8ON2.HC1,  28.43  per  cent. 

1  Ztschr.phys.  Chem.,  4,  326  (1891)  and  Ber.  d.  chem.  Ges.,  34,  4117  (1901). 

2  Ztschr.phys.  Chem.,  5,  17  (1892). 

3  Walker  (/.  Chem.  Soc.  (Condon)  83,  (1903)),  since  this  was  written,  has  calculated  the 
affinity  constant  of  urea  on  the  basis  of  a  new  set  of  more  careful  experiments  and  found 
K  =  1.5  X  io— *<  .    This  value  is  so  near  the  one  calculated  in  the  text  that  we  have  let  the 
latter  stand. 

*  The  affinity  constant  of  water.  K  =  CHCg  O°H    is  one  fifty-fifth  of    its  dissociation 

constant,  K  =  CH  X  COH. 

&  Bredig:  Ztschr.phys.  Chem.,  13,  294,  and  foot-note  p.  293  (1893). 
«  Ostwald :  J.  prakt.  Chem.,  33,  367. 


33 

The  conductivity  measurements  made  with  this  salt  at  25°  are 
given  in  Table  III. 

TABUS  III. 

Af.  AOO- 

v.  I-  II.  I.  II. 

32      99-Jo       99.24  114.1     114.2 

64      102.72      103.19  114.5     ii5-o 

128      106.59      106.71  115.2     115.3 

256      107.60      107.60  114.0     114.0 

512        III. 20         110.33  II5-5       II4.6 

1024    [114.28]    [114.17]  [117.5]   [117.4] 


Means  (excluding  v  =  1024):  114.7  114.6 

t<*P=  II4-7  — 75.9  =  38.8. 

The  extreme  molecular  conductivity  of  the  free  base  A«>  is 
the  sum  of  38.8  and  195.8  (the  extreme  mobility  of  hydroxl  ions), 
or  234.6. 

The  free  base  obtained  according  to  the  method  of  Stieglitz  and 
McKee  was  tested  for  purity  with  the  following  result : 

0.0902  gram  substance  required  10.15  cc.  tenth-normal  HC1. 
Calculated,  10.23  cc- 

The  conductivity  measurements  and  the  calculation  of  the  affin- 
ity constant,  K,  follow : 


1 

'ABLE  IV. 

A».                             looa. 

I05 

K. 

V. 

I. 

ii. 

i. 

II. 

I. 

II. 

8 

6.73 

6.70 

2.87 

2.86 

10.6 

10.5 

16 

9.58 

9.41 

4.09 

4.02 

10.9 

10.5 

32 

1341 

13.18 

5-72 

5-63 

10.9 

10.5 

64 

18.74 

18.37 

8.00 

7.84 

10.9 

10.4 

128 

25.91 

25.34 

1  1.  06 

10.80 

10.8 

10.0 

256 

35.56 

34.30 

15-18 

14.64 

10.6 

10.0 

Means :  10.8        10.3 

Ethyl  isourea  is,  therefore,  nearly  twice  as  strong  a  base  as 
methyl  isourea.  It  is  interesting  to  observe  that  the  substitution 
of  an  ethyl  for  a  methyl  group  attached  to  oxygen  has  caused  a 
much  more  decided  increase  in  the  affinity  constant  than  is  the 
case  when  a  similar  single  substitution  is  effected  for  a  methyl 
group  attached  to  nitrogen  (the  constants  for  methyl  and  ethyl 
amine  are  0.00x350  and  0.00056  respectively). 

Methyl  Phenylisourea,  C6H.NHC(OCHB)  :  NH.— Pure  redis- 
tilled methyl  phenylisourea  was  dissolved  in  absolute  ether  and 


34 

a  slight  excess  of  dry  hydrogen  chloride  added.  The  salt  was 
washed  with  absolute  ether  and  dried  in  vacuo  over  concentrated 
sulphuric  acid  and  solid  potassium  hydroxide  for  several  days. 
Its  water  solution  was  then  neutral  to  sensitive  litmus  paper.  The 
analysis  gave  18.90  per  cent.  Cl.  Calculated,  18.99  Per  cent- 

The  conductivity  measurements  made  with  this   salt  at   25° 
are  given  in  Table  V. 

TABUS  V. 


A". 

Aoo- 

V. 

I. 

II 

III. 

I. 

II. 

in. 

32 

90.36 

90-33 

89.79 

105.4 

105.3 

105.8 

64 

94-49 

94-35 

94.66 

106.3 

106.1 

106.5 

128 

96.85 

96.85 

96.64 

105.5 

105.4 

105.2 

256 

98.87 

98.82 

98.79 

105-3 

105.2 

105.2 

512        101.07     101.22     100.97        105.4     105.5     105.3 

1024  102.55        102.67         102.40  105  71       105.8        105.6 

Means  :  105.6         105.6         105.6 

4,p=  105.6  —  75-9  =  29.7. 

The  extreme  molecular  conductivity  of  the  free  base,  AW  i-s 
the  sum  of  29.7  and  195.8  (the  extreme  mobility  of  hydroxyl 
ions),  or  225.5. 

For  the  measurements  of  the  conductivities  of  the  free  methyl 
phenylisourea,  the  latter  was  purified  by  two  redistillations.  The 
base,  after  it  was  dried  for  two  days  in  vacuo,  gave  the  following 
test  for  purity : 

0.2627  gram  substance  required  17.54  cc.  tenth-normal  HC1. 
Calculated,  17.49  cc. 

The  measurements  and  the  calculation  of  the  affinity  constant, 
K,  follow : 

TABT.E  VI. 


At'. 

iooa.                            10°  K. 

V. 

I. 

II. 

I. 

n. 

I. 

II. 

8 

0.307 

0.31 

0.136 

0.138 

0.022 

0.024 

16 

0.440 

0.445 

0.195 

0.198 

0.024 

0.024 

32 

0.627 

0.634 

0.278 

0.282 

0.024 

0.025 

64 

0.909 

0.905 

0.404 

0.402 

0.026 

0.025 

128 

I-33I 

I-33I 

o.59i 

Q.591 

O.O27 

0.027 

256 

2.056 

2.017 

0.913 

0.896 

0.026 

O.O32 

Means :    0.025        0.026 
The  affinity  constant  of  methyl  phenylisourea  is,  therefore,  only 

1  It  is  noteworthy,   but  not  unexpected,    that  in  this  case  there  is  no  abnormal 
increase  of  the  molecular  conductivity  (see  foot-note  p.  459). 


35 

one-three  hundredth  that  of  methyl  isourea.  It  is  five  hundred 
times  greater  than  that  of  aniline1  (K  —  5  X  io~10).  The  de- 
terminations show  that  it  is  not  sensibly2  hydrolyzed  in  dilute 
solution  and  the  neutrality  to  sensitive  litmus  paper  and  litmus 
solution  confirms  this  view. 

Ethyl  Phenylisourea,  C6H5NHC(OC2H5)  :##.— Ethyl  phenyl- 
isourea  hydrochloride  was  prepared  in  exactly  the  same  way  as 
the  methyl  derivative.  A  water  solution  of  the  salt  was  neutral  to 
sensitive  litmus  and  a  chlorine  determination  gave  17.76  per  cent. 
Cl.  Calculated,  17.57  per  cent. 

Table  VII  gives  the  conductivity  measurements  made  with  the 
salt  at  25°. 

TABUS  VII. 
A.V.  Aoc  • 

V.  I.  II.  I.  II. 

32  88.70  89.38  103.7  104.4 

64  92.86  92.86  104.8  104.7 

128  95.90  95.90  104.5  104.5 

256  97.51  97.51  103.9  103.9 

512  99.67  100.15  104.0  104.4 

1024  101.43  101.44  104.6  104.6 


Means:    104.1  104.6 

1XP=  104.3—  75.9  =  28.4. 

The  extreme  molecular  conductivity  of  the  free  base,  Aoo»  *s 
the  sum  of  28.4  and  195.8  (the  extreme  mobility  of  hydroxy! 
ions),  or  224.2. 

Ethyl  phenylisourea  was  prepared,  purified,  and  tested  for 
purity  exactly  as  the  methyl  derivative. 

0.4806  gram  substance  required  29.30  cc.  tenth-normal  HC1. 
Calculated,  29.27  cc. 

The  measurements  and  the  calculation  of  the  affinity  constant, 

K,  follow : 

TABUJ  VIII. 
\v  looor.  io5  K. 

t/.s  I.  '     II.  I.  II.  I.  II. 

26.03  0.822  0.822  0.367  0.367  0.052       0.052 

52.07  1.118  1.108  0.499  °-498  0.048        0.048 

104.13  1.580  1.571  0.705  0.701  0.048        0.048 

208.26  2.314  2.285  1.032  1.019  0.052        0.050 

416.53  3-469  3-383  1.548  1.510  0.058        0.056 

833.06  5.406  5.253  2.412  2.344             

Mean  :    0.051  ;      0.051 
1  Bredig  :  Loc.  «'/.,  p.  322. 

*  Within  the  limits  of  the  sensitiveness  of  the  measurements. 

3  An  error  was  made  in  calculating  the  amount  of  the  base  necessary  for  a  N/32  solu- 
tion. The  volumes,  v,  given  are  those  actually  used. 


36 

Here  again  the  substitution  of  the  ethyl  for  the  methyl  group 
doubles  the  strength  of  the  base. 

For  his  interest,  constant  aid  and  advice,  I  wish  here  to  express 
my  great  sense  of  obligation  and  gratitude  to  Professor  Stieglitz. 


OF  THI 

1   UNIVERSITY  ] 


OVERDUE. 

wir  1934 


LD  21-100m-7,'33 


YC  39910 


i    ^i 


